Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.C[O-].[Na+].CO.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=O.Cl.[CH:26]1[C:31]([NH:32][NH2:33])=[CH:30][CH:29]=[C:28]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:27]=1.Cl>O.CC(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:32]([C:31]3[CH:26]=[CH:27][C:28]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:29][CH:30]=3)[N:33]=[C:3]([C:2]([F:1])([F:8])[F:9])[CH:15]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(F)cc2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
The following procedure describes a method of preparing the crystal Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide without isolating the crystal Form II. 2-propanol (70 ml) and ethyl trifluoroacetate (27.15 g, 0.191 moles) are added to a first vessel, followed by a line wash of 2-propanol (10 ml). Next, 25% sodium methoxide in methanol (37.5 g, 0.174 moles) is added to the vessel, followed by a line wash of 2-propanol (10 ml). Next, 4-fluoroacetophenone (20 g, 0.145 moles) is added followed by a line wash of 2-propanol (10 ml). The contents of vessel are heated to 55° C. and held at that temperature for 2 hours, then cooled to ambient temperature. Water (110 ml), concentrated hydrochloric acid (20.0 g, 0.203 moles), and 4-sulfonamidophenylhydrazine hydrochloride (32.4 g, 0.145 moles) are added to a second vessel, followed by a line wash of water (10 ml). The contents of the first vessel are added to the second vessel, followed by a line wash of 2-propanol (60 ml). The combined contents are heated at 70° C. for 2 hours, then cooled to 55° C. and seeded with 10 mg (0.05% wt/wt relative to 4-fluoroacetophenone) of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide. The contents are held at 55° C. for 6 hours, then cooled to ambient temperature and filtered. The product is washed with 50% aqueous 2-propanol (120 ml) and water (60 ml), then dried under vacuum at 55° C. to give 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide of the desired Form I polymorph (44.8 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]1[O:15][C:14]2[C:9](=[CH:10][C:11]([N+]([O-])=O)=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[O:8]1.C(N(CC)CC)C.C(O)C>C(O)(=O)C>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:11]1[CH:10]=[C:9]2[O:8][CH2:7][O:15][C:14]2=[CH:13][C:12]=1[N+:16]([O-:18])=[O:17]
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2c(cc1NCC(O)CO)OCO2
Temperature: 0 °C

Procedure:
0.6 mol (56.3 g) of 3-amino-1,2-propanediol is added dropwise to a mixture, brought to reflux, prepared by adding 0.3 mol (63.6 g) of 4,5-methylenedioxy-1,2-dinitrobenzene and 46 ml of triethylamine to 90 ml of 96° strength ethanol. The reaction mixture is heated for 3 hours under reflux. After dilution with 600 ml of ice-cold water and neutralization with acetic acid, the expected product is drained. After recrystallization from acetonitrile, it melts at 120°-121° C.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=1.C(O)C.[OH-].[K+].Cl>O>[CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 5 g. of ethyl 4-(13,13-dimethyltetradecyl)aminobenzoate in 75 ml. 95% ethanol is saponified with 2.5 g. of 85% potassium hydroxide by refluxing for 5 hours. The warm solution is diluted with 150 ml. water and adjusted to pH 5 with 37% hydrochloric acid. The precipitate is filtered, washed with water, dried in vacuo and crystallized from acetic acid to yield the title compound as a cream-colored, amorphous solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([C:14]([OH:16])=O)[C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:17]C(N)=O>O>[O:1]1[C:6]2=[CH:7][C:8]3[C:14](=[O:16])[NH:17][C:11](=[O:12])[C:9]=3[CH:10]=[C:5]2[O:4][CH:3]=[CH:2]1
Reactant: NC(N)=O
Reactant: O=C(O)c1cc2c(cc1C(=O)O)OCCO2
Solvent: O
Product: O=c1[nH]c(=O)c2cc3occoc3cc12
Yield: 88.3 %

Procedure:
A mixture of 1,4-benzodioxan-6,7-dicarboxylic acid (100 mg) and urea (54 mg) was heated to 160° for 2 h. When cool, the mixture was diluted with water and the resulting solid collected by filtration and washed with water and dried to afford the title compound (80 mg). M.p. 277°-280°.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C[CH2:14][C:15]([CH2:20][O:21][CH2:22][CH:23]=[CH2:24])(CO)CO.[C:25]([OH:30])(=[S:29])[CH:26]([CH3:28])[OH:27]>CO.C1(C)C=CC=CC=1.CCCCCC>[CH2:20]([O:21][CH2:22][CH:23]=[CH2:24])[CH:15]=[CH2:14].[C:25]([OH:30])(=[S:29])[CH:26]([CH3:28])[OH:27]
Reactant: C=CCOCC(CC)(CO)CO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(O)C(O)=S
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CCOCC=C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
AIBN (1.5 g) was dissolved in trimethylolpropane monoallyl ether (497 g, 2.86 mol). This solution was slowly added, under nitrogen with stirring, to thiolactic acid (300 g, 2.83 mol) at such a rate that the temperature of the exothermal reaction was kept at 80° C. When the addition was completed, the temperature was raised to 90° C. and kept at 90° C. for 1 h. The product had 1H-NMR (CDCl3): δ 1.11 (t, 3H, CH3CH2), 1.53 (q, 2H, CH3CH2), 2.00-2.20 (m, 2H, CH2CH2CH2), 2.98-3.06 (m, 2H, 3.65-4.02 (m, 9H); and is soluble in methanol and toluene, not soluble in hexane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH2:34]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21][NH:34][CH3:33])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(Cc3ccccc3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1
Solvent: C1CCOC1
Product: CNC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 91 %

Procedure:
Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (5.0 g, 0.0102 mmol) were dissolved in 2.0 M solution of MeNH2 in THF (35 mL) in an autoclave and heated to 80° C. over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, dichloro methane/methanol 0->20%) to yield the title compound (3.25 g, 91%) as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:25]2/[C:24](=[O:26])[NH:23][C:22](=[O:27])[S:21]/2)=[CH:7][CH:6]=1
Reactant: COc1ccccc1C(O)COc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1C(O)COc1ccc(/C=C2\SC(=O)NC2=O)cc1
Yield: 80.2 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.81 g, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [Cl-].C(OC(NCC/C(/N1CCCC1)=C/C(OCC)=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28]1[C:32]2[C:33](=[O:37])[NH:34][CH:35]=[CH:36][C:31]=2[O:30][N:29]=1>>[O:30]([C:31]1[CH:36]=[CH:35][C:27]([C:28]2[C:32]3[C:33](=[O:37])[NH:34][CH:35]=[CH:36][C:31]=3[O:30][N:29]=2)=[CH:28][CH:32]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(/CCNC(=O)OCc1ccccc1)N1CCCC1
Reactant: Cc1noc2cc[nH]c(=O)c12
Agent: [Cl-]
Product: O=c1[nH]ccc2onc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
The title compound was prepared from 4-phenoxybenzohydroxyiminoyl chloride, prepared using the procedure described in Jones, Raymond C. F. et al, J. Med. Chem. 2003, 46, 87–96, and ethyl (Z)-5-{[(benzyloxy)carbonyl]amino}-3-tetrahydro-1H-1-pyrrolyl-2-pentenoate, prepared using the procedure described in Natale, Nicholas, R. et al, J. Chem. Soc. Perkins Trans. I, 1999, 765–776, using a manner similar to that described in Natale, Nicholas, R. et al, J. Chem. Soc. Perkins Trans. I, 1999, 765–776 for the preparation of 3-methyl-4,5-dihydroisoxazolo[4,5-c]pyridin-4-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 2H), 7.66 (d, 1H), 7.46 (t, 2H), 7.22 (t, 1H), 7.1–7.15 (m, 5H), 6.82 (d, 1H); Rt=3.03 min (Conditions a), MS m/e: 303 (M−H)−.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[CH2:6]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([C:16]([O:18]CC)=O)=[O:15])=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].[OH:23][C:24]1[C:25](=O)[O:26][C:27](C)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=1O>C1COCC1>[OH:18][C:16]1[C:14]([C:13]2[CH:12]=[CH:11][C:10]([CH2:6][CH:7]([CH3:8])[CH3:9])=[CH:22][CH:21]=2)([CH2:1][CH2:2][CH3:3])[O:15][C:24](=[O:23])[C:25]=1[O:26][CH2:27][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Reactant: CCC[Mg]Br
Reactant: CC1(c2ccccc2)OC(=O)C(O)=C1O
Solvent: C1CCOC1
Product: CCCC1(c2ccc(CC(C)C)cc2)OC(=O)C(OCc2ccccc2)=C1O

Procedure:
A total of 5.2 mL (10.4 mmol) of 2.0 M 1-propylmagnesium bromide was added to a solution of 2.3 g (10 mmol) of ethyl 4-isobutylbenzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 4-hydroxy-5-(4-isobutylphenyl)-3-phenylmethoxy-5-(1-propyl)-2(5H)-furanone as an oil, which was purified over SiO2 using acetone/hexanes (1/4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].CO[C:17]([C:19]1[C:27]2C(=CC=CC=2)NN=1)=O>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH:19]([CH3:27])[CH3:17])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: COC(=O)c1n[nH]c2cc(Br)ccc12
Product: COC(=O)c1nn(C(C)C)c2cc(Br)ccc12

Procedure:
The title compound is prepared essentially as described in procedure 1d WO2005/080389 substituting 6-Bromo-1H-indazole-3-carboxylic acid methyl ester for 1H-indazole-3-carboxylic acid methyl ester. ES/MS m/e 296.0 (M+1).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].CCCCCC.CCOCC>C(O)C>[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1ccc(O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(O)c(CO)c1
Yield: 69 %

Procedure:
To a suspension of sodium borohydride (2.50 g, 65.8 mmol) in ethanol (100 mL) at 5° C. was added a solution of 2-hydroxy-5-methoxybenzaldehyde (10.00 g, 65.8 mmol) in ethanol (35 mL) dropwise. Upon completion of the addition the reaction mixture was allowed to stir for ten minutes then quenched by the dropwise addition of 10% aqueous acetic acid (75 mL). The ethanol was removed by concentration in vacuo and the resulting mixture poured into water (250 mL) and extracted with ethylacetate (3×100 mL). The combined extracts were washed sequentially with saturated sodium bicarbonate (50 mL), and brine (3×100 mL). The organic extract was dried (Na2SO4) and concentrated to afford a crude product (8.75 g). Trituration with hexane:ether (3:2, 25 mL) afforded 2-hydroxy-5-methoxybenzyl alcohol (7.00 g, 70%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][N:40]=1>O1CCCC1>[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:12]=4)=[N:6][N:5]3[CH:30]=2)=[O:44])=[CH:41][N:40]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)c4ccc(Cl)nc4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 77.4 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol), 6-chloronicotinoyl chloride (76 mg, 0.435 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (155 mg, 77%) was obtained as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1[OH:34].[O-]O.C1(C(C)C)C=CC=CC=1>N1C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:34])=[N:15][CH:16]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 22 °C

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) and (1R,2S)-(+)-1-amino-2-indanol (22.8 mg, 0.151 mmol) are solubilised in anhydrous pyridine (0.65 mL); titanium isopropoxide (IV) (22 μL, 0.076 mmol) is added under stirring at 22° C., followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][O:36][CH2:37][CH:38]=[CH2:39])[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[CH2:37]([O:36][CH2:35][C:20]1[CH:21]=[C:22]([Cl:34])[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:24][C:19]=1[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]1)[CH:38]=[CH2:39]
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (246 mg, 0.39 mmol) in THF:MeOH:H2O (2:3:1, 6 mL) was added LiOH.H2O (16.4 mg, 0.47 mmol). After being stirred for 12 h at room temperature, the reaction mixture was concentrated and the residue was dissolved in 20 mL of EtOAc. The organic layer was washed with brine and dried over Na2SO4 Concentration gave a residue, which was purified by preparative TLC (PE:EtOAc:MeOH=8:80:1, Rf=0.5) to yield 132 mg of title compound as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.42 (s, 1H), 7.11 (s, 4H), 5.93-5.87 (m, 1H), 5.24 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.11 (dd, J=1.6 Hz, 10.4 Hz, 1H), 4.85 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.51 (d, J=9.2 Hz, 1H), 4.23 (s, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.88 (d, J=12.4 Hz, 1H), 3.71-3.67 (m, 1H), 3.52-3.41 (m, 4H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); LC-MS (m/z) 463 [(M+1)+], 507 [(M+45)−].
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.CO.C(Cl)Cl>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CCN2C(=O)c3ccccc3C2=O)n(Cc2ccccc2)n1
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(CCN)n(Cc2ccccc2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
2-[2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethyl]-isoindole-1,3-dione (80 mg, 0.233 mmol) was dissolved in ethanol (2 ml) followed by the addition of an 1M solution of hydrazine in methanol (0.34 ml, 0.34 mmol). The reaction mixture was stirred at 90° C. for 16 h, cooled to rt and DCM (3 ml) was added and the suspension was filtered. The filtrate was concentrated under reduced pressure to give 40 mg (80%) 2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethylamine. LC-MS: tR=0.58 min; [M+H]+=216.38.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.N1CCCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:30]1([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: C1CCCNCC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCCCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), azepane (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:33][C:31]1[CH:30]=[C:22]([O:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:21]=[C:20]([F:19])[C:32]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(F)cc(OC2CCOCC2)c1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(OC3CCOCC3)cc2F)OC1(C)C
Yield: 33 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 equiv.), butyllithium (1.3 equiv.) and 4-(3,5-difluorophenoxyl)tetrahydro-2H-pyran (1.0 equiv.) to give 2-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 33% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.21-1.34 (m, 12 H), 1.78 (dtd, J=12.72, 8.31, 8.31, 3.91 Hz, 2 H), 1.93-2.09 (m, 2 H), 3.59 (ddd, J=11.64, 8.31, 3.13 Hz, 2 H), 3.89-4.01 (m, 2 H), 4.48 (tt, J=7.78, 3.77 Hz, 1 H), 6.40 (d, J=9.39 Hz, 2 H).
Reaction SMILES: [C:1]([CH:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5]1)(O)=[O:2].S(Cl)([Cl:20])=O.[NH3:22]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:2])[NH2:22]
Reactant: O=S(Cl)Cl
Reactant: N
Reactant: O=C(O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Product: NC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 2 in the section relating to the preparation of starting materials 3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted with thionyl chloride and then concentrated aqueous ammonia. The product so obtained was recrystallised from ethanol to give 3-carbamoyl-4-chloro-8-nitroquinoline in 79% yield, mp 277-279° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 44 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 4,4-diphenylbutyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 44%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(C)c1C
Reaction time: 36 h

Procedure:
To a solution of 2,3-dimethylphenol (25.0 g, 205 mmol) in dimethylsulfoxide (200 mL) were added ethyl 2-bromo-isobutyrate (60 mL, 409 mmol) and potassium carbonate (56.5 g, 409 mmol) at room temperature, and the mixture was stirred for 36 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude oily ethyl 2-(2,3-dimethylphenoxy)-2-methylpropionate. 12 N Aqueous sodium hydroxide solution (20 mL, 240 mmol) was added to the mixed solution of this compound in THF (160 mL) and methanol (40 mL) at room temperature, stirred for 12 hours, and then concentrated under reduced pressure. Water and hydrochloric acid were added to the reaction solution to acidity the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was crystallized from ethyl acetate-hexane to obtain 21.3 g (yield 50%) of the title compound. Melting point: 71-73° C.